Improved Outcomes in Myeloma With High-Dose Melphalan Plus Autologous Transplant and Lenalidomide Maintenance
In a phase III trial reported in The New England Journal of Medicine, Palumbo et al found that consolidation therapy with high-dose melphalan plus autologous stem cell transplantation improved progression-free survival and overall survival compared with melphalan/prednisone/lenalidomide (Revlimid) consolidation and that lenalidomide maintenance vs no maintenance improved progression-free survival in patients ≤ 65 years newly diagnosed with multiple myeloma.
Study Details
In this open-label trial, 273 patients aged ≤ 65 years with newly diagnosed multiple myeloma from 62 centers in Israel and Italy were randomly assigned between November 2007 and July 2009 to receive high-dose melphalan (200 mg/m2) followed by autologous stem cell transplantation (n = 141) or melphalan/prednisone/lenalidomide consolidation (n = 132) after induction therapy with lenalidomide and dexamethasone. Of these, a total of 251 were further randomly assigned to lenalidomide maintenance after high-dose melphalan consolidation (n = 67) or melphalan/prednisone/lenalidomide consolidation (n = 59), or no lenalidomide maintenance after high-dose melphalan (n = 68) or melphalan/prednisone/lenalidomide (n = 57). The primary endpoint was progression-free survival.
Progression-Free Survival and Overall Survival
Median follow-up was 51.2 months. Median progression-free survival from time of diagnosis was 54.7 months in patients who received high-dose melphalan plus lenalidomide maintenance, 37.4 months in those receiving high-dose melphalan without maintenance, 34.2 months in those receiving melphalan/prednisone/lenalidomide plus lenalidomide maintenance, and 21.8 months in those receiving melphalan/prednisone/lenalidomide without maintenance. The respective 5-year overall survival rates were 78.4%, 66.6%, 70.2%, and 58.7%.
Prolonged Survival With High-Dose Melphalan
From the start of consolidation, median progression-free survival was 43.0 months in the high-dose melphalan/autologous stem cell transplantation group vs 22.4 months in the melphalan/prednisone/lenalidomide consolidation group (hazard ratio [HR] = 0.44, P < .001) and 4-year overall survival was 81.6% vs 65.3% (HR = 0.55, P = .02). The progression-free survival benefit associated with high-dose melphalan was consistent across all patient subgroups.
Lenalidomide Maintenance
From the start of maintenance, median progression-free survival was 41.9 months with lenalidomide maintenance vs 21.6 months without maintenance (HR = 0.47, P < .001). Three-year overall survival was nonsignificantly prolonged with lenalidomide maintenance (88.0% vs 79.2%, HR = 0.64, P = .14).
Toxicity
Grade 3 or 4 adverse events that were significantly more common with high-dose melphalan (all P < .001) included neutropenia (94.3% vs 51.5%), thrombocytopenia (93.6% vs 8.3%), gastrointestinal events (18.4% vs 0%), infections (16.3% vs 0.8%), and systemic events (12.8% vs 1.5%). Grade 3 or 4 adverse events that were more common with lenalidomide maintenance vs no maintenance included neutropenia (23.3% vs 0%, P < .001), infections (6.0% vs 1.7%, P = 0.09), and dermatologic events (4.3% vs 0%, P = 0.03). Treatment was discontinued due to adverse events in 4% of patients during induction and in 0.7% during high-dose melphalan treatment and 3.0% during melphalan/prednisone/lenalidomide treatment. Adverse events led to lenalidomide dose reduction in 14.7% of patients and discontinuation in 5.2%. Second primary cancers were observed in 0.3% of patients during induction, in no patients during high-dose melphalan or melphalan/prednisone/lenalidomide consolidation, and in 4.3% of both the lenalidomide maintenance and no maintenance groups during the maintenance period.
The investigators concluded: “[W]e found that consolidation therapy with high-dose melphalan, as compared with melphalan/prednisone/lenalidomide, improved progression-free and overall survival, although at a cost of increased toxicity. Our findings confirm that high-dose melphalan remains the more effective therapeutic option in patients with newly diagnosed multiple myeloma. We also found that maintenance therapy with lenalidomide, as compared with no maintenance therapy, significantly reduced the risk of disease progression.”
Antonio Palumbo, MD, of the University of Turin, is the corresponding author for The New England Journal of Medicine article.
The study was funded by Celgene. For full disclosures of the study authors, visit www.nejm.org.
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